Radiation poses a significant threat to public health from either accidental or deliberate exposures, proving lethal at higher doses due primarily to the effects on hematopoiesis. When irreversible injury to the bone marrow occurs hematopoietic cell transplantation is required for survival, and realistically after unplanned high-level exposure, this would be carried out within 2 to 4 days following injury, precluding attempts at identifying human leukocyte antigen (HLA) matched unrelated donors from existing registries. Therefore the most relevant sources of stem cells in such a setting would be offspring or parents of the victim who would either be HLA matched or, more likely, be HLA mismatched. We have previously reported preclinical studies in a canine model demonstrating that HCT from major histocompatibility (MHC) matched littermates was lifesaving after radiation exposure. The proposed studies will use the preclinical canine model to expand on this work and to develop therapy to rescue victims of unplanned radiation exposure by testing the hypothesis that HCT can be achieved across MHC barriers from HLA haploidentical donors. The significance of these studies is underpinned by the failure of previous attempts at HCT after radiation accidents and they will be based on already existing MHC mismatched HCT strategies by including rapid donor stem cell mobilization and the use of novel pharmacological immunosuppression to facilitate engraftment and control graft versus host disease. The first specific aim will define the barrier to HCT engraftment imparted by varying doses of myeloablative total body irradiation (TBI) and delayed administration of hematopoietic stem cells. The second aim expands upon these findings by evaluating additional maneuvers to overcome the host versus graft barrier consisting both of innate (NK cells) and adaptive (T cells) immunities. The third aim develops regimens to both control GVHD and enhance donor HCT engraftment. At the conclusion of these studies we anticipate having developed methods that allow for consistent engraftment of MHC-haploidentical cells after accidental total body irradiation exposure of marrow-lethal intensity without significant GVHD. The development of such methods will ensure that large numbers of people could receive concise and definitive therapeutic regimens to treat lethal radiation injury.